Novel <scp><i>DIP2C</i></scp> gene splicing variant in an individual with focal infantile epilepsy

Le, Yang; Zhao, Siyu; Ma, Nan; Lang, Liang; Li, Dongjing; Li, Xia; Wang, Zhijing; Song, Xixiao; Wang, Yan; Wang, Dong

doi:10.1002/ajmg.a.62524

Cited by 3 publications

(9 citation statements)

References 26 publications

(32 reference statements)

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“…All the examined patients had developmental difficulties ( n = 11) or language disorder ( n = 10) (Descipio et al 2012 ). A recent study reported a case of a 17-month-old female with focal infantile epilepsy, dysmorphic features, and developmental delays in motor developmental coordination and in receptive and expressive language (Yang et al 2022 ). WES identified the de novo variant NM_014974.3 (DIP2C): c.1057 + 2T>G that was shown by minigene transfection assay to lead to DIP2C alternative splicing and an 80 bp deletion in Exon 8 (Yang et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study reported a case of a 17-month-old female with focal infantile epilepsy, dysmorphic features, and developmental delays in motor developmental coordination and in receptive and expressive language (Yang et al 2022 ). WES identified the de novo variant NM_014974.3 (DIP2C): c.1057 + 2T>G that was shown by minigene transfection assay to lead to DIP2C alternative splicing and an 80 bp deletion in Exon 8 (Yang et al 2022 ). Furthermore, we detected two loss-of-function DIP2C variants in two ASD individuals upon mining published genetic data from 16,877 ASD individuals (Zhou et al 2022 ).…”

Section: Discussionmentioning

confidence: 99%

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Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2024

Hum. Genet.

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Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. We did not detect significant associations between the language-related tests and language-related PRS. Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the condition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2024

Hum. Genet.

View full text Add to dashboard Cite

show abstract

“…c.1057 + 2T > G that was shown by minigene transfection assay to lead to DIP2C alternative splicing and an 80 bp deletion in Exon 8(Yang et al, 2022). Furthermore, we detected two loss of function DIP2C variants in two ASD individuals upon mining published genetic data from 16,877 ASD individuals(Zhou et al, 2022).PARD3 is essential for cell polarity and nervous system development (X Hirose et al, 2022)…”

mentioning

confidence: 83%

“…All the examined patients had developmental di culties (n = 11) or language disorder (n = 10)(Descipio et al, 2012). A recent study reported a case of a 17-month-old female with focal infantile epilepsy, dysmorphic features, and developmental delays in motor developmental coordination and in receptive and expressive language(Yang et al, 2022). WES identi ed the de novo variant NM_014974.3 (DIP2C): Chinese family manifesting nonsyndromic isolated cleft palate.…”

mentioning

confidence: 99%

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia,

Li,

Lejerkrans

et al. 2023

Preprint

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Background Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Methods Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. Results We identified clinically significant variants in five probands, resulting in a 9.4% (5/53) molecular diagnostic yield. Those variants were in CHD3, PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. However, we detected positive associations between neurodevelopmental difficulties and PRS for educational attainment and cognitive performance within the families (p = 0.006 and 0.02, respectively). We did not detect significant associations between PRS for language quantitative measures and their corresponding PRS. Conclusion Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the conditions.

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“…The clinical description included asthma and migraines in addition to autism, but further details were not provided. Thus, although there is some evidence that DIP2C plays a role in cognition, reports of pathogenic variants in this gene are rare (Yang et al, 2022).…”

mentioning

confidence: 99%

De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay

Ha,

Morgan,

Bartos

et al. 2024

American J of Med Genetics Pt A

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The disconnected (disco)‐interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase‐associated protein 1 (DMAP1) binding domain, Acyl‐CoA synthetase domain and AMP‐binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco‐interacting protein 2 homolog A (DIP2A), Disco‐interacting protein 2 homolog B (DIP2B), and Disco‐interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss‐of‐function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss‐of‐function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10–24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss‐of‐function variants in DIP2C with a neurocognitive phenotype.

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Novel DIP2C gene splicing variant in an individual with focal infantile epilepsy

Cited by 3 publications

References 26 publications

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay

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